Compositions including a cannabinoid and protocatechuic acid

ABSTRACT

A composition comprising a therapeutically effective amount of a cannabinoid and protocatechuic acid is provided. The disclosure further provides a method of treating inflammation comprising administering a composition comprising a therapeutically effective amount of a cannabinoid and protocatechuic acid to a patient in need thereof. The disclosure further provides a method of treating inflammation including administering a composition including protocatechuic acid and a composition including a cannabinoid to a patient in need thereof. In embodiments, the composition including protocatechuic acid and the composition including a cannabinoid may be administered simultaneously within about 60 minutes of each other. In embodiments, the cannabinoid includes Cannabidiol (CBD).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/225,584, filed on Apr. 8, 2021, which is herein incorporated byreference in its entirety.

BACKGROUND OF THE DISCLOSURE Field of the Invention

This disclosure is generally directed to compositions including acannabinoid and protocatechuic acid and methods of treatment using thecompositions. In preferred embodiments, the methods of treatment mayinclude treating inflammation. In preferred embodiments, the cannabinoidmay include Cannabidiol (CBD).

Description of the Related Art

Cannabinoids are a class of compounds found in cannabis.Phytocannabinoid tetrahydrocannabinol (THC) is a cannabinoid and isregarded as a primary psychoactive compound in cannabis. Cannabidiol(CBD) is another major cannabinoid. There are known to be at least 144different cannabinoids.

Synthetic cannabinoids are also known. They encompass a variety ofchemical groups including those structurally related to THC, as well ascannabimimetics including aminoalkylindoles, 1,5-diarylpyrazoles,quinolines, and arylsulfonamides, as well as eicosanoids which arerelated to endocannabinoids. Cannabidiol (CBD) is a phytocannabinoid. Itcan account for up to 40% of a cannabis plant's extract.

Cannabidiol (CBD) as a therapeutic can be administered to a mammal in avariety of ways, including inhalation, by oral delivery, transdermal, aswell as through an aerosol. It may be supplied as CBD oil, or hemp oil(extract), or in capsules, dried cannabis, and is also available as aprescription liquid solution. CBD is not known to have the samepsycho-activity as THC. In the United States, the cannabidiol drugEpidiolex™ was approved by the Food and Drug Administration for thetreatment of epilepsy disorders. The effects of CBD on receptors in theimmune system may help reduce overall inflammation in the body. CBD oilmay offer benefits for acne management. CBD oil may prevent activity insebaceous glands. CBD may also prevent cancer cell growth. CBD may alsohave benefit for neurogenerative disorders.

Protocatechuic acid (PCA) is a dihydroxybenzoic acid. Protocatechuicacid (PCA) is known as an antioxidant and anti-inflammatory. PCA hasbeen variously reported in the literature as having a variety of healthbenefits.

SUMMARY OF THE INVENTION

A composition comprising a therapeutically effective amount of acannabinoid and protocatechuic acid is provided. The disclosure furtherprovides a method of treating inflammation comprising administering acomposition comprising a therapeutically effective amount of acannabinoid and protocatechuic acid to a patient in need thereof. Thedisclosure further provides a method of treating inflammation includingadministering a composition including protocatechuic acid and acomposition including a cannabinoid to a patient in need thereof. Inembodiments, the composition including protocatechuic acid and thecomposition including a cannabinoid may be administered simultaneouslywithin about 60 minutes of each other. In embodiments, the cannabinoidincludes cannabidiol (CBD).

The cannabinoid may include a cannabigerol-type compound,cannabichromene-type compound, cannabidiol-type compound,tetrahydrocannabinol and cannabinol-type compound, cannabielsoin-typecompound, iso-tetrahydrocannabinol-type compound, cannabicyclol-typecompound, and/or a cannabicitran-type compound.

The cannabinoid may include tetrahydrocannabinol (THC),tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolicacid (CBDA), cannabinol (CBN), annabigerol (CBG), cannabichromene (CBC),cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabiorcol (THCC),tetrahydrocannabivarin (THCV), tetrahydrocannabiphorol (THCP),cannabidivarin (CBDV), cannabichromevarin CBCV, cannabigerovarin (CBGV),cannabigerol monomethyl ether (CBGM), cannabielsoin (CBE), and/orcannabicitran (CBT).

In preferred embodiments, the cannabinoid includes cannabidiol (CBD). Inpreferred embodiments, the cannabinoid is cannabidiol (CBD).

PCA is a powerful antioxidant and anti-inflammation reagent.Inflammation is fundamental to all disease. CBD can be used as anadjunct to PCA while providing medicinal properties not known to PCA.

The pharmacology of CBD in not completely known. Side effects areminimal as reported, but still under investigation. The pharmacology ofPCA is well established and PCA has no known adverse side effects; noallergy, no mutagenic, no toxicity. In embodiments, the combination ofPCA and CBD allows the dose of CBD to be low or well within the knownrange, yet still achieving health benefits.

Other features and aspects will be apparent from the following detaileddescription and the claims.

DETAILED DESCRIPTION

The following detailed description is provided to assist the reader ingaining a comprehensive understanding of the methods, products, and/orsystems, described herein. However, various changes, modifications, andequivalents of the methods, products, and/or systems described hereinwill be apparent to an ordinary skilled artisan.

This disclosure is directed to compositions including cannabinoids andprotocatechuic acid. The cannabinoids may include any of the class ofcompounds generally recognized as cannabinoids deriving from thecannabis plant. In a preferred embodiment, the cannabinoid may becannabidiol. The cannabinoids may be a naturally occurring compound orcan be prepared synthetically.

Cannabinoids may interact with, or mediate, the cannabinoid receptorsCB1 and/or CB2. The cannabinoids may also interact with the‘endocannabinoid system’ which consists of cannabinoid receptors, aswell as ligands of cannabinoid receptors (endocannabinoids) and variousenzymes. The endocannabinoid system is involved in many importantphysiological functions in the central and peripheral nervous systemsand in the endocrine and immune systems of a mammal.

Cannabinoids may be extracted from a plant with organic solvents.Hydrocarbons and alcohols may be used. Supercritical solvent extractionwith carbon dioxide may also be used. Once extracted, isolatedcomponents can be separated using distillation or other standardseparation techniques. As mentioned above, cannabinoids of thedisclosure may also be synthetically prepared. A standard CBD crystal isabout 4.44 micrometers (4,440 nanometers). Whereas, Nano CBD is lessthan 100 nanometers.

The cannabinoids of the disclosure may include the following classes ofcompounds: Cannabigerol-type, Cannabichromene-type, Cannabidiol-type,Tetrahydrocannabinol and Cannabinol-type, Cannabielsoin-type,iso-Tetrahydrocannabinol-type, Cannabicyclol-type, andCannabicitran-type.

Cannabinoids of the disclosure include: Tetrahydrocannabinol (THC),tetrahydrocannabinolic acid (THCA), Cannabidiol (CBD), cannabidiolicacid (CBDA), Cannabinol (CBN), Cannabigerol (CBG), cannabichromene(CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabiorcol(THCC), tetrahydrocannabivarin (THCV), tetrahydrocannabiphorol (THCP),cannabidivarin (CBDV), cannabichromevarin CBCV, cannabigerovarin (CBGV),cannabigerol monomethyl ether (CBGM), cannabielsoin (CBE), cannabicitran(CBT).

Cannabinoids of the disclosure may have anti-inflammatory,antioxidative, antiemetic, antipsychotic, and/or neuroprotectiveproperties. Cannabinoids of the disclosure may be able to treat anxiety,addiction, appetite, sleep disorders, pain perception, nausea, andvomiting. Cannabinoids of the disclosure may treat osteoarthritis.Cannabinoids of the disclosure may be useful for pain management.Cannabinoids of the disclosure may be useful for the treatment ofcancer.

Compositions of the disclosure may treat redox balance by modifying thelevel and activity of both oxidants and antioxidants. Compositions ofthe disclosure may interrupt free radical chain reactions, capturingfree radicals or transforming them into less reactive forms.

The treatments may encompass inflammatory, nociceptive, and neuropathicpain. CBD is an exogenous (out of the body) cannabinoid that acts on theendogenous (in the body) cannabinoid system to function in anantioxidant capacity, decrease inflammation and act as an analgesic.

Treatment with compositions of the disclosure may slow the progressionof osteoarthritis by decreasing inflammation, both systematically andlocally. The interaction of compositions of the invention with theimmune system and its potential antioxidant affect helps to decreasesymptoms associated with osteoarthritis and improve quality of life.

Administering compositions of the invention can block pain signals fromreaching the brain by binding to specific pain receptors. Administeringcompositions of the invention may attenuate central sensation andneuropathic pain development. Administering compositions of theinvention may decrease pain sensations locally by reducingmechanosensitivity of joint nociceptors. Administering compositions ofthe invention may reduce joint swelling and decrease immune cellinfiltration, inflammation, and thickening of the connective tissue thatlines joints. Administering compositions of the invention may reduceacute, inflammatory changes. Administering compositions of the inventionmay reduce production of inflammatory cytokines. Administeringcompositions of the invention may relieve anxiety and sleep disturbancesassociated with chronic pain conditions.

The mechanism of action may differ between PCA and CBD. PCA may work byan anabolic stimulation by increasing the genetic expression of thegrowth hormone IGF-1 and other anabolic cytokines; IL-4 and IL-10. Atthe same time, inflammatory catabolic cytokines are reduced. CBD may actas a serotonin receptor partial agonist. It is an allosteric modulatorof the μ and δ-opioid receptors as well. The pharmacological effects ofCBD may involve PPARγ agonism, inhibition of voltage-gated cationchannels, and intracellular calcium release.

Protocatechuic acid (PCA) is a phytochemical, a powerful antioxidant,which is found in nature. There are no known human toxic effects of PCA.PCA is non-allergenic and a non-inflammatory. It is also non-mutagenic.Importantly for a new therapeutic, protocatechuic acid (PCA) has beendesignated as Generally Recognized As Safe (GRAS) by the FDA as a foodflavoring substance. PCA may be biochemically manufactured and/orextracted from plants in an amorphous or crystalline state. Both stateshave anti-viral properties of low pH, anti-protease, docking blocker andhormonal and cellular immunity remains inherent in the molecule.

As mentioned, protocatechuic acid (PCA) is a compound with powerfulanti-inflammatory properties. One of the ways the human body responds toPCA is with a massive anti-inflammatory response. The pathologicaleffect seen in clinical cases of SARS Co-2 has been termed a ‘cytokinestorm’ in the lungs. PCA is a powerful anti-inflammatory by itsanti-catabolic cytokine blocker properties. PCA acts as a tyrosinaseinhibitor in other applications. PCA is also a protease inhibitor. PCAhas anti-viral docking properties.

Protocatechuic acid (PCA) is thus a broad-spectrum antiviral destroyingantibiotic when coating of cloth and/or metal surfaces. PCA crystalshave the physical properties of a crystal with sharp protrusions thatmay disrupt the coating of microbes in the dry state or in solution.Protocatechuic acid (PCA) has a viricidal effect on the SARS CoV2 virus.SARS CoV-2 virus retains its viability and pathogenesis in aqueousmedium; in animals, humans and in air borne droplets.

The compositions of the invention can be administered in a variety ofways, including, by oral delivery, inhalation, intravenous, topical, andtransdermal, an aerosol including an oromucosal spray, pulmonaryadministration, as well as nanotechnology-based approaches. Thetherapeutic compositions and compounds may be administered, for example,by buccal, injection, pulmonary, inhalant, subcutaneous, and sublingualdelivery.

The present invention also provides compositions that may beadministered to localized affected areas of a mammal as well. This wouldinclude the skin, lungs, and nasal cavities. The present disclosure alsoprovides compositions and methods for use in the treatment of symptomsrelated to Covid-19.

In embodiments the administration may be by intraperitoneal routes. Alsodisclosed is a method of treating a pathological condition comprisingthe coating of skin, oral cavity, nares, nasopharynx, and pulmonary treewith compositions of the invention.

In embodiments, the present disclosure provides multiple routes oftherapeutic delivery. Normal size crystals (e.g., approximately 177 μmor micrometer or 40 times larger than CBD) and powder may be deliveredby an oral route. Smaller sized crystals and particles may also be usedfor intravenous, intraperitoneal and aerosol delivery to a patient. Bycomparison a red blood cell is approximately 7.5 to 8.7 μm in diameterand 1.7 to 2.2 μm in thickness.

Further by way of example, the pharmaceutical composition can comprise apharmaceutically acceptable carrier. By way of example, thepharmaceutically acceptable carrier can be selected from, but notlimited to, any carrier, diluent, or excipient compatible with the otheringredients of the composition.

Further by way of example, the pharmaceutical composition can comprisean acceptable delivery carrier. By way of example, the delivery can beformulated and administered as known in the art, e.g., for topical,oral, buccal, including lozenges, injection, intravenous, inhalant,subcutaneous, sublingual and/or transdermal. Further, said topicaldelivery carrier may be formulated and administered to any surface orcavity of the body.

By way of example, the acceptable delivery can be selected from anydermal or transdermal carrier compatible with the other ingredients ofthe composition. In some embodiments, the acceptable delivery carrier isa biodegradable microsphere or a slow release bioabsorbable material. Byway of example, the acceptable delivery carrier can be selected from50/50 D, L lactide/glycolide or 85/15 D, L lactide/glycolide, both ofwhich are amorphous physically and, therefore, are non-reactive whenused as a carrier in a composition that is delivered in or to the body.

In embodiments, the pharmaceutical composition may be formulated for anaerosol spray. The aerosol spray may include a liquid vehicle and astabilizer. The liquid vehicle may include water, or an alcohol and thestabilizer may include an oil. In preferred embodiments, the oil is anessential oil. In preferred embodiments, the essential oil may be lemonoil. In embodiments, the aerosol spray compositions may compriseprincipally the active ingredients, liquid vehicle, and stabilizer asthe main ingredients.

In embodiments, the administration of the cannabinoid and theprotocatechuic acid may be by the same route. In embodiments, theadministration of the cannabinoid and protocatechuic acid may be bydifferent routes and may be simultaneous or essentially simultaneous.

Simultaneous as used herein means that both compositions will beadministered such that both compositions (or their metabolites) will besubstantially present in the body of the patient at the same time. Thismay thus encompass administration at the same time or at nearly the sametime, for example, within about 60 minutes of each other, or preferablywithin about 30 minutes, or more preferably within about 15 minutes.

For example, the cannabinoid and the protocatechuic acid may be in asingle composition or formulation, e.g., a pill or tablet, or the like.In other embodiments, the cannabinoid and the protocatechuic acid may beadministered separately. For example, the protocatechuic acid may be ina pill or tablet and the cannabinoid may be administered transdermally.

A pharmaceutical composition as used herein generally refers to amedication (also referred to as medicine, pharmaceutical drug, medicinaldrug or simply drug) and that is used to diagnose, cure, treat, orprevent disease. See Medicine, Wikipedia, The Free Encyclopedia, Date oflast revision: 21 Mar. 2021, herein incorporated by reference.

The metabolism of cannabinoids and PCA is to enter the body bypotentially different routes but both go to the liver and becomemetabolized. The various metabolites perfuse the body and are eventuallyeliminated via the kidney (urine) or bowel (feces).

Bio availability of each in the body are different and thereforepresents a need for combination to maximize the effect. The oralbioavailability of cannabidiol is approximately 6% in humans whilebioavailability by inhalation is 11-45% (mean of 31%).

The oral availability of PCA is 100% in 30 minutes. Therefore, differentroutes may be complementary depending upon a patient's condition; forinstance, in a burn case the topical route would not be available, butinhalation would. When inhalation is not available, then oral could beused for both. In the alternative, the CBD route could be by inhalationand/or skin and PCA by oral delivery. Intravenous and intra peritonealare also available for PCA.

The duration of each in the body is different. The elimination half-lifeof CBD is 18-32 hours. PCA has a peak at 2 minutes and life of 8 hours.The duration planning in therapeutic prescriptions is important for peakeffects and duration thereof to achieve maximum benefit.

In certain embodiments, the route of administration is oral. Powderedactive ingredient can be mixed with a suitable liquid for drinking orgavage or alternatively, the active ingredient can be in the form of apill or capsule. The active ingredient may also be mixed with othersolid eatable ingredients, such as for an example, in a nutrition/snackbar.

For purposes of the present invention, a pharmaceutical composition ispreferably formulated in a unit dosage and in an injectable or infusibleform such as solution, suspension, or emulsion. It can also be in theform of a lyophilized powder, which can be converted into solution,suspension, or emulsion before administration. In some embodiments apharmaceutical composition is provided in a formulation that includesbiodegradable microspheres or of amorphous bioabsorbable material ofglucose itself. The common biodegradable carriers are importantlyamorphous physically and as opposed to crystalline material, do notcause tissue irritation.

In some preferred embodiments the composition is administered togetherwith 50/50 D, L. lactide/glycolide or 85/15 D, L lactide glycolide. Alsoencompassed herein are nanospheres as known in the pharmaceutical arts.The pharmaceutical compositions may be sterilized by membranefiltration, autoclaving, irradiation and the like and may be stored inunit-dose or multi-dose containers such as sealed vials or ampules. As anon-limiting example, a dose pack may contain 3-5 vials foradministration. The first injected initially at the office or at surgerythen the remaining vials to be administered over time, such asperiodically over weeks. In some instances, glucose may form a portionof the delivery vehicle, whereupon release it enhances thechondroreparative features of the composition.

Methods of formulating pharmaceutical compositions are generally knownin the art and are applicable with the instant invention. For instance,the active ingredients may be mixed together with the pharmaceuticallyacceptable carrier or salt. Thorough discussions of formulationdevelopment and selection of pharmaceutically acceptable carriers,stabilizers, coloring, and flavoring agents and like can be found in avariety of pharmaceutical texts known to those skilled in the art, suchas Remington's Pharmaceutical Sciences (Mack Publishing Co., Eaton,Pa.), the contents of which are herein incorporated by reference in itsentirety.

In some embodiments, the compositions of the present invention areformulated in a sustained-release formula to prolong the presence of thecompounds in the treated subject, generally for longer than one day.Many methods of preparing sustained release formulations are known inthe art and are available in a variety of publications, includingRemington's Pharmaceutical Sciences, cited and incorporated by referenceabove. In some instances, the active ingredients and optionally glucoseis trapped in semipermeable matrices of solid hydrophobic polymers. Thematrices can be shaped into films, coatings, microcapsules, ormicrospheres and administered as known by those skilled in theappropriate art. Any suitable ratio may be used, which may in partdepend on the desired matrix. As a nonlimiting example, thepharmaceutical may be provided with a biodegradable polymer formed fromabout 85/15 or 50/50 D, L lactide/glycolide. The matrices may be avariety from a variety of materials; solids and meshes.

EXAMPLES

Protocatechuic acid (PCA) and cannabidiol (CBD) are new reagents withhealth and wellness benefits. There is a need for the combination ofthese drugs to deliver their shared benefits of being an antioxidant andanti-inflammatory reagents. In addition, each have independent benefitsnot found in the other, whereby the combination synergistically bringsall the benefits of each.

Various vehicles were tested with each and in combination. The belowdata shows that propylene glycol and an alcohol provide an excellentvehicle for combination. Distilled and deionized water are restricted inamounts independently and when placed in combination. The combination ofPCA and CBD can be delivered companionably.

Protocatechuic acid (PCA) and cannabidiol (CBD) can be combined fortherapeutic purposes. PCA and CBD have recently emerged as novel healthand wellness reagents. They are phytochemicals in the nutraceutical,food supplement category. Antioxidants are fundamental to health.Inflammation is the basis of all disease. Each of these reagents havediffering additional pharmaceutical properties that would complementeach other for a potential important role in health and wellness.

PCA is generally water soluble, but not oil soluble. CBD is oil basedand therefore soluble in oil but has restricted solubility in water.Various means can be used to increase the solubility of CBD in water.Emulsification is one method, but is not necessarily a water-solubleproduct, only water compatible. Another method produces an isolate ofCBD. The isolate is a fine powder produced by glycosylation or theattachment of a sugar molecule. The isolate is closer to water soluble.

There is a need in this context to select a pharmacological liquidvehicle that will provide an optimal dose of when combined. Variousevidence would condition the manufacturing of the combinations;preliminary low-level warming of the vehicle, while avoidingtemperatures above 100 degrees Fahrenheit.

Basic science studies have shown PCA to stimulate human and animalsynovium to produce IGF-1 a growth hormone that acts as a diseasemodifying osteoarthritic drug (DMOAD). There is further evidence thatPCA is a broad-spectrum antibiotic, a biofilm destroyer and hasantiviral properties including SARS CoV2. Furthermore, itsanti-inflammatory properties extend to inflammation of the human skin,including action as an antiseptic for skin pathogens, including C.acnes. PCA in human and animal experiments demonstrate the properties toincrease the expression of local growth factors; resulting in woundhealing, cartilage repair, and accelerated bone growth. There isadditional evidence that PCA has beneficial therapeutic effect uponcellular and hormonal immunity.

CBD is from the hemp plant. It is manufactured with restriction of thepsychoactive tetrahydrocannabinol (THC). CDB may have 0-3% THC. THC isthe main psychoactive cannabinoid found in cannabis and common tomarijuana. CBD is not psychoactive.

CBD has been reported to benefit a wide variety of health issues. CBD iseffective in treating some of the cruelest childhood epilepsy syndromes,such as Dravet syndrome and Lennox-Gastaut syndrome (LGS), whichtypically don't respond to antiseizure medications. In numerous studies,CBD was able to reduce the number of seizures, and in some cases it wasable to stop them altogether. Recently the FDA approved the first evercannabis-derived medicine for these conditions, Epidiolex™, whichcontains CBD.

CBD is commonly used to address anxiety, and for patients who sufferthrough the misery of insomnia, studies suggest that CBD may help withboth falling asleep and staying asleep.

CBD treats different types of chronic pain. CBD applied on the skin mayhelp lower pain and inflammation due to arthritis. CBD inhibitsinflammatory and neuropathic pain, two of the most difficult types ofchronic pain to treat.

Solubility

PCA: The solubility of PCA is known in water (1.24%), isopropyl alcohol(30%), denatured ethanol (30%), and propylene glycol (15%). It is notknown in deionized water. It is generally not soluble in oil.

CBD: CBD is soluble in oil by nature of the oil-based hemp product.Solvents such as ethanol, methanol, DMSO, and dimethyl formamide purgedwith an inert gas can be used. The solubility of cannabidiol in thesesolvents is approximately 35, 30, 60, and 50 mg/ml, respectively.

Materials: The materials were 99% pure PCA and a proprietary 98% purewater-soluble CBD isolate with zero percent HTC. The liquid vehiclesused are considered G.R.A.S. by FDA; distilled water, deionized water,propylene glycol and 70% isopropyl alcohol. The test containers were125-milliliter graduated and measured sterile plastic from Wheatoncompany. A thermometer probe was used to assess the temperatures.

Method: The first experiment was to identify the PCA and CBD crystals bymicroscopically, including polarized light. Each crystal was visualizedin dry state, followed by soaking crystals on a histology glass slide indistilled water, deionized water, propylene glycol, and isopropylalcohol. This provided a base line for physical shapes of each of theregents; CBD and PCA for future identification when both are insolution.

The physical properties of each were easily identifiable by polarizedlight microscopy. It was learned they have distinct physical propertiesunder polarized light microscopy for identification.

PCA has a sharp spear like physical shape. CBD has clusters of thickrod-shaped crystals often on top of each other. Both showed varyingamounts of color when refracted by polarized light.

An additional method was employed to replicate the clinical topicalapplication. A smear of the various concentrations was made on the glasshistology blank slide to show the amount of crystals deployed for thevarious concentrations.

CBD crystals were observed in deionized water. PCA crystals wereobserved in propylene glycol. 10× Polarized light microscopy inspectionclearly shows the different physical shapes of each.

Testing was done to determine the independent solubility of each reagentin the various vehicles. This was followed by testing the potentialconcentrations of each when combined. The testing started with anarbitrary solution concentration, one that could be altered forpercentage of solubility.

CBD Solubility Testing

Oil: CBD isolate is naturally oil soluble. It will fully dissolve thewhite powder into any oil. Warming and or stirring or shaking may berequired to move the isolate into solution. It usually takes about 10-15minutes to fully dissolve. Combined testing in oil was not performed asPCA is not soluble in oil.

Distilled Water: Distilled water is a possible vehicle. CBD was testedat 1.0 gram (1%) in 100 milliliters of distilled water. CBD did notreadily dissolve in 100 ml of distilled water at room temperature of 69degrees Fahrenheit. Heating to 120 degrees Fahrenheit was necessary fordissolving. Upon cooling the CBD went out of solution. There was CBD onthe wall of the plastic container throughout; at the sides and bottomwith a glue-like tan material. There was a ring around the inside of thecontainer at the level of the water. There was CBD spattered coating ofthe container wall above the fluid line. There was a reaction during theheating that produced a gas that caused the sealed plastic container toexpand. Loosening of the cap gave relief to the expanded plasticcontainer to return to original configuration.

1 gram of CBD in 50 ml distilled water after cooling showed the reagenttotally coating the inside of the container; a tan glue-like material onbottom and the sides. There was bead like coating above the water line,delivered by the gaseous state.

The next test was performed in a similar manner with a reduced amount ofwater-soluble CBD isolate to 0.247 milligrams (0.247%). It did notreadily dissolve in 100 ml of distilled water at room temperature of 69degrees Fahrenheit. Heating to 120 degrees Fahrenheit was necessary fordissolving. Heating prior to adding the CBD proved to be a moreeffective method to hasten the solubility. Upon cooling the CBD went outof solution. There was CBD on a wall of the plastic containerthroughout; at the sides and bottom with a glue-like tan material. Therewas a ring around the inside of the container at the level of the water.There was CBD spattered coating of the container wall above the fluidline. This was anticipated during the procedure as there was a reactioncausing the sealed container to expand as though gas was produced.Loosening of the cap gave relief to the expanded plastic container toreturn to original configuration.

A reduction to 0.247 gram CBD in distilled water produced the sameresult.

A further reduction in concentration was used in the next experiment; 40milligrams of CBD in distilled water. 40 mg is the recommended dailyoral dose of CBD. Heating to 105 Fahrenheit did not dissolve. Itrequired 140 degrees Fahrenheit to dissolve. No gaseous expansionoccurred as with larger concentrations. This is only a 0.04% CBD. Forreference, PCA is 1.24% soluble in distilled water.

Deionized water: 1.025 grams of CBD was placed in 50 milliliters ofdeionized water at room temperature water. It only went into solution at120 Fahrenheit. After cooling all the CBD came out of solution withsimilar appearance as distilled water. The failure was as 2.05 grams per100 ml or a 2.05% solution.

1.025 grams CBD isolate in 50 ml. deionized water shows failure of goinginto solution.

Therefore, a similar test was performed with a lesser amount of CBD;0.517 milligrams of water-soluble CBD in 50 milliliters of deionizedwater. Preliminary heating of the water facilitated the CBD intosolution. Upon cooling and 24 hours later, the CBD was still insolution. The percentage of CBD isolate in solution was 1.34% CBD indeionized water. This is similar to distilled water. It also is similarin percentage to PCA which is 1.24% in water. 0.5 grams CBD in deionizedwater remained in solution for at least 48 hours in this test.

Propylene glycol: Initial testing with propylene glycol was at 2 grams(4%) in 50 milliliters of propylene glycol. This did not go intosolution even with heating. The expansion of the plastic capped bottlehappened indicating gas production. Removal of lid resulted inexpression of gas and return of the bottle to original shape. Thenpropylene glycol was added to the 100-milliliter level. The procedurewas repeated and then 2% CBD went into solution with the same gaseousexpansion and release. Upon cooling the CBD came out of solution.

2 grams of CBD in 50 ml. propylene glycol was not dissolved even onheating.

The test was repeated with lesser amount of CBD; 1-gram (1%) CBD in 100milliliters of propylene glycol. This went easily into solution withpreliminary heating to 120 Fahrenheit. CBD remained in solution past 48hours after cooling.

1 gram of CBD in 100 ml of propylene glycol remained in solution beyond48 hours.

Alcohol: Ethanol and or isopropyl alcohol is used for industrialextraction of CBD from the hemp fiber. Therefore, it has a very highsolubility in alcohol. Initial testing was performed at 1%concentration.

1.02 gram of CBD in 100 ml of isopropyl alcohol was soluble more than 48hours. It also was performed with 3 grams CBD in 97 ml of 70% isopropylalcohol.

3 grams of CBD in 100 ml of 70% isopropyl alcohol remained soluble morethan 48 hours.

Results: The dry raw material of PCA and water-soluble CBD isolate maybe combined in any ratio for potential prescription purposes. However,the route and/or vehicle may present restrictions or limitations onvarious combinations in the following liquid vehicles.

Distilled water: CBD was soluble at only 0.04%. PCA is 1.24% soluble indistilled water.

Deionized water: CBD (1.34%) and PCA (1.24%) are similar in solubilityin deionized water.

Propylene glycol: CBD is soluble at 1% while PCA is soluble up to 15% inpropylene glycol.

Isopropyl alcohol: 1.024 mg (1%) to 3 grams of CBD isolate in 70%isopropyl alcohol was readily absorbed at room temperature (68 degreesFahrenheit) and/or with mobilization of the crystals with minimalshaking. No heating was required.

Testing of Smear on Glass Slide: This clearly demonstrated that 1%concentrations of CBD showed very sparse crystals. The concentrations of2 and 3% showed abundant crystals of both CBD and PCA.

Heating caused a gaseous reaction that expanded the capped container.

Subsequent Testing on Combinations: Based upon the above individualfindings further testing was done on the combinations of the tworeagents to seek maximum concentrations in combination for clinicalapplications.

Propylene Glycol: The first test was the combination of equalproportions of 0.5 grams of CBD and PCA in propylene glycol. Propyleneglycol is a commonly used FDA G.R.A.S. reagent in the food industry in awide variety of consumer products.

1: An attempt to replicate the solubility of 1 gram, 0.497 mg CBD and0.501 mg of PCA put on top of 99 ml of propylene glycol in a sterileplastic container. The CBD floated on top. When the PCA was added bothreagents went to the bottom without dissolving. The reagents went intosolution quickly after a few moments of shaking. Importantly heating wasnot necessary.

0.50 grams CBD and 0.49 grams of PCA in 100 ml propylene glycoldissolved in solution for more than 48 hours.

2: Then tested CBD at increased amounts; its known maximum of 1% (1.04gm) in propylene glycol with PCA at 1% (0.97 gram). The PCA firstfloated and fell to bottom. The CBD went to bottom and in tan globule.Shaking mobilized into suspension and gradually settled to the bottom.Heated for 30 seconds to 140° F. Minimal shaking caused all fewparticles to go into solution. There was no gaseous expansion observed.The combination of 1 gram each of CBD and PCA remained in solution morethan 48 hours.

Deionized water: The next test was the combination of equal proportionsof 1.0 grams of CBD and PCA in deionized water. Deionized water is acommonly used FDA G.R.A.S. reagent for topical applications and someoral prescriptions.

0.993 grams of CBD added to 20 seconds heated 98 milliliters deionizedwater (100 degrees Fahrenheit). Then 1.1 PCA added. Not dissolved.Shaking left powder at water level in jar. Temperature to 95° F. and notdissolved. Temp to 120° F. and not dissolved as floating on top ofwater. So, heated further to 140 Fahrenheit. The tan “glue” adhered tothe sides and at the water level.

This amount of CBD and PCA did not go into solution. A tan glue-likematerial was often seen following heating of CBD in solution.

Note: It appears that CBD solute when heated past 100 Fahrenheit forms atan “glue” like material.

The amounts were reduced to PCA 0.493 and CBD to 0.506 grams. The PCAinto room temperature deionized water went to bottom and partiallymixed. The CBD floated on top of water. Shaking would not mix. Heatingto 100 degrees F. and 120 degrees F. did not mix the CBD and tan glue onthe sides. This lesser amount of PCA and CBD did not go into solution,plus there was the tan glue of CBD on the sides of the container.

The amounts were further reduced to PCA 0.26 and CBD to 0.243 grams. ThePCA into room temperature deionized water went to bottom and partiallymixed. The CBD floated on top of water. Shaking would not mix. Heatingto 100 degrees F. and 120 degrees F. did not mix the CBD and tan glue onthe sides. Even this lesser amount of PCA and CBD did not go intosolution, plus there was the tan glue of CBD on the sides.

Further reductions in amounts of the combination in deionized waterwould likely be below a therapeutic level of PCA, even as only 40milligrams of CBD is the recommended daily oral dose. A furtherreduction may be tried for topical application, but then the thresholdof CBD would be far below the 1 to 3 gram amounts.

These reagents could be administered separately in deionized water.

Distilled water: The 0.04% of CBD in distilled water is very limiting inconcentration so its combination with PCA was deferred to a later time.CBD at 40 mg could be used separately by oral route. The 1.24% of PCAmay be used in distilled water independently.

Alcohol: 3 grams of CBD and 3 grams of PCA were placed in 94 millilitersof 70 isopropyl alcohol at room temperature. Most went into solutionimmediately. Shaking of the vial resulted in the few clumps to go intosolution. This combination concentration exceeds dose parameters ofeach.

3 grams of CBD and 3 grams of PCA in 100 ml isopropyl alcohol remainedin solution for more than 48 hours.

Microscopic Inspection of Combinations of CBD and PCA: This alcoholsolution was used to identify the two individual crystals within thesolutions. A swab of the 3 grams of CBD and 3 grams of PCA in 70%isopropyl alcohol was examined under polarized light. There wereabundant crystals of both reagents. Visualization during the dryingphase on the histology glass slide showed the sudden expansion of thespike shaped PCA; virtually growing during the drying phase. Theclinical significance is the immediate presence of the PCA shapes thatdisrupt the skin of microbes leading to death. Abundant crystals wereeasily identified.

The following polarized light photomicrographs were obtained:

Polarized light photomicrograph of PCA and CBD crystals; 4×;

Polarized light photomicrograph of PCA and CBD crystals; 40×;

Polarized light photomicrograph of CBD crystals; 4×;

Polarized light photomicrograph of CBD crystals; 10×;

Polarized light photomicrograph of PCA and CBD crystals; 10×;

Polarized light photomicrograph of CBD crystals; 40×;

Polarized light photomicrograph of PCA crystals 10×;

Polarized light photomicrograph of CBD and PCA crystals 40×.

The above polarized light photomicrographs demonstrated that theindependent crystalline physical shapes remain intact in a combinationof PCA and CBD delivered in solution.

PCA and the commonly available oil-based CBD dry raw materials may bephysically combined at any ratio for therapeutic purposes. The dose anddelivery route may be oral, intra venous, or intraperitoneal, andtopical pending the clinical condition under consideration.

The combination of dry CBD isolate powder and PCA crystals may becombined physically in any ratio for similar purposes.

The exploration of dry raw material combinations in solution wasconditioned by the reported prescribed dose of each depending upon theapplication. For an oral route, there is no unsafe practical limit forPCA. The usual oral dose of PCA is delivered in a 500 mg capsule,liquid, gummy, or tablet. The amount per day may be up to 2 tablets fourtimes a day, providing under health care supervision. The recommendeddaily oral dose of CBD is 20-40 milligrams.

The use of a liquid vehicle for PCA and CBD delivery places conditionsheretofore unknown on the doses and concentrations and were identifiedin this study. The nature of the different vehicles places limitationsof dose and concentration on PCA and CBD independently and incombination.

The combination solubility testing is only possible with use of awater-soluble CBD isolate since PCA is not easily soluble in oil. Thesolubility of each of the reagents and their reaction and solubility incombination are now known. The two reagents may differ in solubilityalone and or in combination.

PCA is soluble in water, but not readily soluble in an oil vehicle. CBDis naturally oil based and not readily soluble in a water vehicle. PCAcrystals and the natural oil-based CBD powder are restricted in liquidvehicle combination since an oil and water vehicle do not mix. Attemptsas such would only allow the CBD to be in suspension without solubility.Therefore, any attempts to combine PCA and CBD require the CBD to be awater-soluble CBD powder for any and all potential therapeutic, healthand or wellness preparations.

This example used a proprietary water-soluble CBD solute with PCAcrystals for potential combination prescription purposes.

The prescription amount for topical application allows a more widelydiverse amounts of PCA and CBD. For instance, a topical dose as small as25 uM PCA is sufficient for controlling a mammalian skin wound of MRSAand Pseudomonas while healing the wound in 2 days. There is no knownupper limit for PCA but a typical concentration is up to a 30%concentration in alcohol vehicle. CBD has no reported lower limit foreffective topical application, but the slide smear test indicates that2-3% concentration would be necessary to leave abundant residual ofcrystals. In arthritis a 3-gram amount is recommended for topicalapplication for treatment of arthritis. This study showed that thisamount in 100 milliliters of isopropyl alcohol showed CBD crystalscompletely covering of the area of application.

The material and the methods of this study were performed with theseparameters in mind. The search for the concentration within each vehiclewas explored searching for the parameters that would be clinicallypractical as well as safe and effective.

Propylene glycol and deionized water liquid vehicle had similarindependent solubility. However, even at concentrations below prescribedamounts, the combination did not go into solution.

There is a similar potential of similar concentration combinations withalcohol since both PCA and CBD allow 30% or more concentrations. Theredoes not appear to be any practical concentration limitation in thecombination in alcohol. In alcohol, based by the literature CBD would beup to 90% plus at the original time of extraction. PCA has up to 30%solubility in 70% isopropyl alcohol and 60% denatured ethanol. 3 gramswas easily and rapidly into solution at room temperature (69 degreesFahrenheit).

The most interesting finding was the limitation of CBD solubility indistilled water at 0.04% while PCA was known to be 1.24% from previousstudies. There is no apparent explanation for the low percentage of CBDin distilled water in this proprietary formula. Other water-soluble CBDsources may be different.

Information was gained concerning manufacturing of CBD alone or incombination. Preliminary heating of the liquid vehicle facilitatedsolubility and therefore would be important in manufacturing. Thepotential for gas expansion with heating is another importantobservation to be addressed during manufacturing even as low as 100degrees Fahrenheit.

This example established the potential ways heretofore unknown ofcombining PCA and CBD for use in clinical medicine. In this study, thepractical optimal amounts of each reagent and vehicle were identified.

In the dry crystal of PCA or powder state of CBD are effectivelycombined physically in any amounts.

The potential for combination of PCA and CBD in various liquid vehiclesshowed great variance. In such cases as below, the optimal combinationmay be best delivered separately in an optimal vehicle. In othervehicles like propylene glycol and iso-propyl alcohol the amounts ofcrystals in solution were up to 15-30% and well beyond the generallyprescribed dose.

A review of each reagent shows widely different solubility concentrationwhen alone or in combination.

Distilled water:

-   -   PCA is soluble up to 1.24%.    -   CBD is soluble up to 0.04%.

The combination was deferred as the low level of CBD concentration wouldlikely be good for oral application which would be preferred.

Deionized water:

-   -   PCA is soluble up to 1.24%.    -   CBD is soluble up to 1.34%.    -   The combination is not soluble at concentrations below        recommended dose.

Propylene glycol:

-   -   PCA is soluble up to 15%.    -   CBD is soluble up to 1%.

The combination was good at concentration level beyond the generallyrecommended dose.

Isopropyl alcohol:

-   -   PCA is soluble up to 30% concentration.    -   CBD is soluble up to 90%+ concentration.    -   The combination was effective at 3% of each, well beyond any        anticipated dose.

Each of the % concentrations in these examples are given by weight.

Based upon the evidence in this example the following vehicles lendthemselves to combining PCA and CBD; propylene glycol and alcohols.

The therapeutic combination had various limitations such that thecombination of delivery would not be in the same vehicles, butseparately; distilled and deionized water.

Information was obtained concerning manufacturing methods. The mosteffective method of rapidly placing either into any vehicular solutionwas pre-heating the liquid to at least 100 degrees Fahrenheit and moreeffectively at 140 degrees Fahrenheit. However, adverse side effectswere seen with some liquids. It was noted that for manufacturing or anyother means of formulation that heating of CBD alone and/or incombination above 90 Fahrenheit results in a tan ‘glue’ or stickymaterial, and therefore is contraindicated. The use of CBD in alcoholsat even a small percentage or other vehicles when heated to put intosolution have the potential to leave a waxy or gum type of residue ifused alone in disinfectants.

PCA did not leave such a residue. PCA leaves an invisible smoothnon-sticky crystalline coating on the article's surface. The PCA may beseen with 1-3% concentrations. PCA is least visible following dryingfrom a 0.25% PCA in alcohol. In water the drying in slower and on smoothvertical surfaces there is a collection of water running as drippinggiving an uneven coating.

Propylene glycol may be a favored vehicle for PCA and CBD, alone or incombination. In addition, propylene glycol is FDA G.R.A.S. and thereforemay be used in most every prescription route. Propylene glycol hasfavorable reports on skin absorption of CBD in the literature even at 1%concentration.

The reported doses for topical application therefore are between 1% and3% depending upon the condition. 1% for skin conditions and 3% forunderlying arthritic conditions.

The alcohols are preferred liquid vehicles for combinations of CBD andPCA since they allow larger concentrations but may be limited to topicalroute applications.

The clinical topical use concentrations of CBD and PCA together orindependently should be at least 3% to leave a concentrated crystallinecovering of reagent.

The examples provide information for manufacture guidelines (e.g.,heating limits) as well as clinical concentrations limitations whencombined. The examples also provide amounts and dosages for use inclinical medicine.

EXAMPLE

A cannabinoid/PCA liquid composition for oral delivery includes acannabinoid/PCA composition from 0.001% to 10% by weight with at leastone optional surfactant from 2-20% by weight, a solvent from 20-70% byweight, an optional preservative and/or flavoring at 0.1-5% each; andthe remainder water. The cannabinoid can be cannabidiol (CBD). Inanother example, the composition comprises two or more surfactants, andthe surfactant(s) may form a self-assembling emulsion.

The surfactants can include oleic acid, sunflower oil, lecithin,phosphatidylcholine, isopropyl myristate, stearic acid, triglycerides,polysorbate, sorbitan trioleate, sorbitan surfactants, and theircombinations. The solvents can include methanol, ethanol, isopropylalcohol, butanol, pentanol, hexanol, ethylene glycol, glycerin,propylene glycol, dipropylene glycol, glycerol, erythritol, xylitol,mannitol, sorbitol, diethylene glycol, monoethyl ether and combinations.

In embodiments, in a liquid mixture or dry tablet, pill, or solidformulation, the cannabinoid may be about 0.001%-50% by weight orpreferably about 0.001%-10% by weight, or about 0.001%-3% by weight orabout 0.001%-1% by weight of the total composition; and the PCA may beabout 0.001%-50% by weight, preferably about 0.001%-25% by weight orabout 0.001%-5% by weight, or about 0.001%-3%, or about 0.001% to about1% by weight of the total composition.

Preferably dosage amounts would be 500 mg PCA and 20-40 mg CBD in acapsule, tablet, gummy or similar ratios in a liquid or drink mixture.

While this disclosure includes specific examples, it will be apparentafter an understanding of the disclosure of this application has beenattained that various changes in form and details may be made in theseexamples without departing from the spirit and scope of the claims andtheir equivalents.

The invention claimed is:
 1. A pharmaceutical composition consisting essentially of a therapeutically effective amount of tetrahydrocannabinol and protocatechuic acid.
 2. The composition of claim 1, wherein the tetrahydrocannabinol is about 0.001% to about 10% by weight of the total composition and the protocatechuic acid is about 0.001% to about 25% by weight of the total composition.
 3. The composition of claim 1, wherein the tetrahydrocannabinol is about 0.001% to about 3% by weight of the total composition and the protocatechuic acid is about 0.001% to about 3% by weight of the total composition.
 4. A method of treating cytokine mediated inflammation comprising administering a composition of claim 1, to a patient in need thereof.
 5. The method of claim 4, wherein the administration comprises oral administration, inhalation, intravenous, topical, transdermal, an aerosol, pulmonary, buccal, injection, subcutaneous, and/or sublingual administration.
 6. The method of claim 4, wherein the tetrahydrocannabinol is about 0.001% to about 10% by weight of the total composition and the protocatechuic acid is about 0.001% to about 25% by weight of the total composition.
 7. The method of claim 4, wherein the tetrahydrocannabinol is about 0.001% to about 3% by weight of the total composition and the protocatechuic acid is about 0.001% to about 3% by weight of the total composition.
 8. The method of claim 4, wherein the cytokine mediated inflammation comprises neuropathic pain, arthritis, skin inflammation and acne, chronic pain, osteoarthritis, wound healing, cartilage repair, inflammatory pain, upper respiratory inflammation, and/or joint swelling.
 9. A method of treating cytokine mediated inflammation comprising administering a composition comprising protocatechuic acid and a composition comprising tetrahydrocannabinol to a patient in need thereof within about 60 minutes of each other or less.
 10. The method of claim 9, wherein the administration of the composition comprising protocatechuic acid and the composition comprising tetrahydrocannabinol is done within about 15 minutes of each other or less. 